Bevacizumab based chemotherapy is a promising option in metastatic gallbladder adenocarcinoma.

Gallbladder cancer (GBC) is one of the most frequently observed cancers in India that is usually diagnosed at an advanced stage. Although surgery remains the only curative option, the majority of GBCs are unresectable. Palliative chemotherapy with gemcitabine and cisplatin is the recommended treatment in such cases. The current study reports a case of a 47-year-old female who exhibited GBC that had metastasized to the liver and peritoneum. She was administered palliative chemotherapy with gemcitabine and cisplatin, but due to disease progression the regimen was changed and an aggressive treatment initiated with gemcitabine and oxaliplatin with additional biosimilar bevacizumab (modified Gemox-B regimen). The patient completed six chemotherapy cycles with partial response and received bevacizumab (7.5 mg/kg 3-weekly) based maintenance treatment for an additional 6 cycles, after which she demonstrated disease progression, thus having a progression free survival of ~11 months. The patient is currently receiving palliative chemotherapy with capecitabine.

Biomarkers in Non-Small Cell Lung Cancers: Indian Consensus Guidelines for Molecular Testing.

Novel molecular targets and promising targeted therapies have reshaped diagnostics in patients with advanced non-small cell lung cancer (NSCLC). Despite this progress, the implementation of molecular screening to identify predictive biomarkers in Indian clinical and pathology settings has been challenging due to operational and logistical constraints. This consensus guideline brings together medical oncologists, molecular pathologists and pathologists from India to provide a quick and competent reference for biomarker testing in NSCLC. The guideline summarizes the importance of targetable mutations in NSCLC such as epidermal growth factor receptor (EGFR), rearrangements in anaplastic lymphoma kinase and receptor tyrosine kinase encoded by ROS-1 gene, overexpression of programmed cell death ligand-1 and resistant EGFR mutations. It reaffirms recommendations from international working groups, discusses vulnerable pre-analytical procedures and provides a balanced review on the pros and cons of different diagnostic tests (immunohistochemistry, fluorescence in situ hybridization, polymerase chain reaction-based testing and next-generation sequencing). The document also provides an algorithm to aid diagnostic decision-making and a checklist to assess the quality of testing laboratories that will help the medical oncologists make an informed choice. Overall, these recommendations are based on evidence and clinical experience and will aid policymakers, oncologists, health care practitioners and pathologists who strive to implement molecular strategies and make informed decisions for improved care in NSCLC in India.Funding: AstraZeneca Pharma India Limited.

Indian Council of Medical Research Consensus Document for the Management of Non-Hodgkin's Lymphoma (High Grade).

This consensus document is based on the guidelines related to the management of Non Hodgkin's Lymphoma (High grade) in the Indian population as proposed by the core expert committee. Accurate diagnosis in hematolymphoid neoplasm requires a combination of detailed history,clinical examination, and various investigations including routine laboratory tests, good quality histology section (of tumor and also bone marrow aspirate/biopsy), immunostaining, cytogenetic and molecular studies and radiology investigations. The staging system used for adult high grade lymphomas is based on the Ann Arbor system and includes various parameters like clinical, haematology, biochemistry, serology and radiology. Response should be evaluated with radiological evaluation after 3-4 cycles and at the end of treatment based on criteria including and excluding PET. Treatment of high grade lymphomas is based on histologic subtype, extent of disease, and age of the patient. Autologous stem cell transplantation after high dose chemotherapy is effective in the treatment of relapsed NHL. Newer RT techniques like 3 dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) can significantly reduce radiation doses to surrounding normal tissues in lymphoma patients. Patients should be followed up every 3 to 4 months for the first 2 years, followed by 6 monthly for the next 3 years and then annually.

Advanced therapeutic options and importance of rebiopsy in epidermal growth factor receptor-tyrosine kinase inhibitor-progressed nonsmall cell lung carcinoma patients: An expert opinion.

Advanced nonsmall cell lung cancer (NSCLC) treatment is primarily based on platinum-based chemotherapy. Although epidermal growth factor receptor (EGFR) targeting has shifted the treatment paradigm toward personalized tyrosine kinase inhibitors (TKIs), resistance develops inevitably and EGFR T790M is the most common acquired resistance mechanism. Rebiopsy of resistant NSCLC cases can provide additional information on the underlying resistant mechanisms and therefore can help clinicians in taking better management decisions. An expert panel meeting of renowned cancer oncologists was held to discuss the management of advanced-stage NSCLC. The present paper is based on the recommendations made by the expert panel and is supported by an exhaustive literature search. It was suggested that identification of driver mutation leads to better treatment decisions. TKIs have proven to be better treatment option in EGFR-positive patients as compared to chemotherapy. Third-generation TKIs (osimertinib) promise to bring optimal and improved care for NSCLC cases failing first-line TKI treatment.

Kodameae ohmeri - An Emerging Yeast: Two Cases and Literature Review.

Kodameae ohmeri is an emerging pathogen in various types of infections. Most infections are seen in patients with compromised immunity like cancer patients. Few cases of neonatal infections due to K. ohmeri have been reported earlier in premature neonates with fatal outcomes. We report two cases of fungemia; the first case was a patient with hematological malignancy, who complained of fever spikes and grew K. ohmeri in blood despite prophylactic voriconazole therapy. The second case was in a mature neonate, who developed respiratory distress and features of sepsis two days after birth, multiple blood cultures were positive for K. ohmeri. Both the patients responded well to Amphotericin B. Repeat blood cultures were sterile and patients were discharged. K. ohmeri is an unusual and emerging fungal pathogen of late an increasing number of cases of fungemia, funguria, endocarditis, peritonitis and wound infections due to the same are being reported. Some occur in immunocompromised patients and some inapparently immunocompetent patients, neonates with an inclination for preterm babies. We report two case of fungemia, one with lymphoma and the second in a neonate.

Saree cancer in Indian woman treated successfully with multimodality management.

Saree is a common, traditional garment of Indian women, wrapped around the waist is tightened by a thick cord and with one end draped over the shoulder. Tight knot in the same place, sweat, soiling and continuous use can cause pigmentation, scaling of the waist and even transform to malignancy. We present here a case of saree cancer successfully managed with multimodality therapy. A 50-year-old woman was referred to our hospital (India) for itching and non-healing ulcerative lesion on waistline. She was wearing saree continuously for 34 years with knot at the same place. Magnetic resonance images suggested ulcerative growth with lymph node metastasis. She then underwent wide local excision; histopathological examination confirmed it was a squamous cell carcinoma. She therefore received concomitant chemotherapy and radiotherapy. She is now (2 years after the completion of treatment) in remission state. Awareness of saree cancer among Indian is important to avoid malignant lesions at waistline. Multimodality management with surgery, chemotherapy and radiotherapy is ideal mean for good outcome.

An elderly woman with triple primary metachronous malignancy: A case report and review of literature.

INTRODUCTION: Prevalence of multiple primary malignancies is slowly increasing due to prolonged survival of cancer patients with advances in diagnostic and therapeutic modalities. The reasons may be environmental modifications, genetic predisposition or therapy induced. We describe a case of a 64-year-old woman with three different metachronous primary malignancies managed at our center since 4 years. PRESENTATION OF CASE: First primary diagnosed in our patient was adenocarcinoma of small intestine which is a rare gastrointestinal malignancy. For this she underwent surgical resection followed by chemotherapy. After 21 months she developed infiltrating duct carcinoma of breast which was managed with modified radical mastectomy and chemotherapy. Again after latent period of 10 months patient had papillary adenocarcinoma of ovary for which she was administered chemotherapy. During follow up tumor was found to be chemoresistant and again she underwent cytoreductive surgery followed by chemotherapy. DISCUSSION: In present case patient did not have significant risk factors for development of carcinoma of small intestine, breast and ovary. Our patient underwent surgical excision three times and received total 16 chemotherapy cycles of different regimens during management of all three primary malignancies. Development of second and higher order primary malignancy after successful management of previous one should be always kept in mind. CONCLUSION: Awareness, suspicion of multiple primary malignancy and aggressive diagnostic work up plays crucial role in their detection at earlier stage for better outcome. In addition choice of appropriate chemotherapeutic agents and their regimens remains the cornerstone while managing the patients with multiple primary malignancies.

A multicenter phase II randomized study of Cremophor-free polymeric nanoparticle formulation of paclitaxel in women with locally advanced and/or metastatic breast cancer after failure of anthracycline.

AIMS: Paclitaxel is extensively used in the treatment of advanced carcinomas of the breast, ovary and non-small cell lung cancer. In clinical use it is formulated in the non-ionic surfactant polyethoxylated castor oil (Cremophor) and dehydrated alcohol to enhance drug solubility. Cremophor adds to toxic effects of paclitaxel by producing or contributing to the well-described hypersensitivity reactions that commonly occur during its infusion, affecting a large number of patients. This randomized trial was conducted to evaluate efficacy and safety of novel nanoparticle-based paclitaxel in the treatment of patients with advanced breast cancer. METHOD: Patients were randomized to receive either nanoparticle paclitaxel (NP) 300 mg/m(2) , (NP300) or NP220 mg/m(2) or Cremophor paclitaxel 175 mg/m(2) (CP 175). NP was administered as a 1-h infusion without premedication and CP as a 3-h infusion with premedication every 3 weeks. RESULTS: In total, 194 patients who had been administered at least one dose were included for safety analysis and 170 patients who completed at least two cycles of therapy were analyzed for efficacy. NP showed an overall response rate (complete response + partial response) of 40% in the NP220 and NP300 arms as compared to 31% in the CP arm. The incidence of neutropenia (all grades) was lowest in the NP220 arm (39.4%) compared to the NP300 (55%) and CP arm (50%). CONCLUSION: NP is well tolerated and can be safely administered without any premedication in comparison to conventional paclitaxel, which requires the use of premedication before administration. NP demonstrates promising efficacy with a favorable safety profile.

Reduced PKC α Activity Induces Senescent Phenotype in Erythrocytes.

The molecular mechanism mediating expression of senescent cell antigen-aggregated or cleaved band 3 and externalized phosphatidylserine (PS) on the surface of aged erythrocytes and their premature expression in certain anemias is not completely elucidated. The erythrocytes with these surface modifications undergo macrophage-mediated phagocytosis. In this study, the role of protein kinase C (PKC) isoforms in the expression of these surface modifications was investigated. Inhibition of PKC α by 30 µM rottlerin (R30) and 2.3 nM Gö 6976 caused expression of both the senescent cell marker-externalized PS measured by FACS analysis and aggregated band 3 detected by western blotting. In contrast to this observation, but in keeping with literature, PKC activation by phorbol-12-myristate-13-acetate (PMA) also led to the expression of senescence markers. We explain this antithesis by demonstrating that PMA-treated cells show reduction in the activity of PKC α, thereby simulating inhibition. The reduction in PKC α activity may be attributed to the known downregulation of PMA-activated PKC α, caused by its membrane translocation and proteolysis. We demonstrate membrane translocation of PKC α in PMA-treated cells to substantiate this inference. Thus loss of PKC α activity either by inhibition or downregulation can cause surface modifications which can trigger erythrophagocytosis.

RhoA: a therapeutic target for chronic myeloid leukemia.

BACKGROUND: Chronic Myeloid Leukemia (CML) is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL) the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL. METHODS: To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters. RESULTS: In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines. CONCLUSIONS: RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a therapeutic target in CML.

Randomized, double-blind, placebo-controlled phase II study of single-agent oral talactoferrin in patients with locally advanced or metastatic non-small-cell lung cancer that progressed after chemotherapy.

PURPOSE: To investigate the activity and safety of oral talactoferrin (TLF) in patients with stages IIIB to IV non-small-cell lung cancer (NSCLC) for whom one or two prior lines of systemic anticancer therapy had failed. PATIENTS AND METHODS: Patients (n = 100) were randomly assigned to receive either oral TLF (1.5 g in 15 mL phosphate-based buffer) or placebo (15 mL phosphate-based buffer) twice per day in addition to supportive care. Oral TLF or placebo was administered for a maximum of three 14-week cycles with dosing for 12 consecutive weeks followed by 2 weeks off. The primary objective was overall survival (OS) in the intent-to-treat (ITT) patient population. Secondary objectives included progression-free survival (PFS), disease control rate (DCR), and safety. RESULTS: TLF was associated with improvement in OS in the ITT patient population, meeting the protocol-specified level of significance of a one-tailed P = .05. Compared with the placebo group, median OS increased by 65% in the TLF group (3.7 to 6.1 months; hazard ratio, 0.68; 90% CI, 0.47 to 0.98; P = .04 with one-tailed log-rank test). Supportive trends were also observed for PFS and DCR. TLF was well tolerated and, generally, there were fewer adverse events (AEs) and grade ≥ 3 AEs reported in the TLF arm. AEs were consistent with those expected in late-stage NSCLC. CONCLUSION: TLF demonstrated an apparent improvement in OS in patients with stages IIIB to IV NSCLC for whom one or two prior lines of systemic anticancer therapy had failed and was well tolerated. These results should be confirmed in a global phase III trial.

A randomized, double-blind, placebo-controlled, phase II study of oral talactoferrin in combination with carboplatin and paclitaxel in previously untreated locally advanced or metastatic non-small cell lung cancer.

INTRODUCTION: The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer. METHODS: Patients (n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety. RESULTS: The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29-47%; p = 0.05) and 15% (27-42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group. CONCLUSION: TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial.

Post-therapy profile of serum total cholesterol, retinol and zinc in pediatric acute lymphoblastic leukemia and non-Hodgkin's lymphoma.

OBJECTIVE: To assess serum albumin, total cholesterol, retinol, zinc and hemoglobin in children who had completed treatment for acute lymphoblastic leukemia (ALL) and Non-Hodgkin's lymphoma (NHL). METHODS: The above parameters were analyzed in 105 ALL and NHL and 108 age and sex-matched controls. Serum albumin, serum cholesterol and hemoglobin were estimated by colorimetric methods. Serum retinol was estimated by HPLC and serum zinc was estimated by atomic emission spectrophotometer (ICP-AES). Comparisons were made to stage of treatment (maintenance 6 with post-therapy), type of treatment (chemotherapy and radiation with only chemotherapy) and type of malignancy (ALL with NHL). RESULTS: Only serum albumin in patients included at Maintenance(6) was significantly higher (t = 2.31, p = 0.05) than post-therapy patients. No significant difference in serum values was observed by type of treatment. Only total cholesterol was significantly higher in NHL patients than in ALL patients (t = 1.954, p = 0.05). Patients had comparable serum levels to that of controls. However, in patients and controls more than 75% children had deficient serum retinol levels, (< than 0.6989 micromol/l, or 20 microg/dl). Further, 75% patients and 54.7% controls had serum retinol levels less than 0.3439 micromol/l or 10 microg/dl. CONCLUSION: The results of the present study indicate that cancer and its treatment did not have any long-lasting effect on serum albumin, total cholesterol, retinol, zinc and hemoglobin. Majority of subjects had low serum retinol suggestive of depleted liver reserves. The deficient serum retinol levels (< than 0.6989 micromol/l, or 20 microg/dl) in at least 75% of the patients and controls probably reflect poor dietary intake. A higher percentage of patients with low serum retinol levels may also be attributed to the possibility of urinary losses of retinol that occur during episodes of infection while on immunosuppressive anti-cancer drug therapy.

Altered Ca2+ homeostasis in polymorphonuclear leukocytes from chronic myeloid leukaemia patients.

BACKGROUND: In polymorphonuclear leukocytes (PMNL), mobilization of calcium ions is one of the early events triggered by binding of chemoattractant to its receptors. Besides chemotaxis, a variety of other functional responses are dependent on calcium ion mobilization. PMNL from chronic myeloid leukaemia (CML) patients that were morphologically indistinguishable from normal PMNL were found to be defective in various functions stimulated by a chemoattractant - fMLP. To study the mechanism underlying defective functions in CML PMNL, we studied calcium mobilization in CML PMNL in response to two different classical chemoattractants, fMLP and C5a. RESULTS: Release of calcium estimated by flow cytometry and spectrofluorimetry using fluo-3 as an indicator showed that the [Ca2+]i levels were lower in CML PMNL as compared to those in normal PMNL. But, both normal and CML PMNL showed maximum [Ca2+]i in response to fMLP and C5a at 10 sec and 30 sec, respectively. Spectrofluorimetric analysis of the total calcium release in chemoattractant treated PMNL indicated more and faster efflux of [Ca2+]i in CML PMNL as compared to normal PMNL. CONCLUSION: Fine-tuning of Ca2+ homeostasis was altered in CML PMNL. The altered Ca2+ homeostasis may contribute to the defective functions of CML PMNL.

Antibodies against 9-O-acetylated sialic acids in childhood acute lymphoblastic leukemia: a two-year study with 186 samples following protocol MCP 943.

Initial studies have revealed an enhanced surface expression of 9-O-acetylated sialoglycoconjugates (9-OAcSGs) on lymphoblasts concomitant with high titers of antibodies (anti-9-OAcSGs) in childhood acute lymphoblastic leukemia (ALL). This study was undertaken in 186 coded samples from 69 ALL patients to evaluate if antibodies against these sialoglycans could monitor response to the treatment. An ELISA was developed using bovine submaxillary mucin (BSM) containing high % of 9-O-acetylated sialic acids (9-OAcSA) as the capture antigen, to investigate serum levels of anti 9-OAcSGs in a single-center series of pediatric, clinically-diagnosed and immunophenotypically confirmed ALL patients, as compared to 130 healthy controls. At presentation, a 3.8-fold increase in anti-9-OAcSGs levels was detected in 63/69 ALL patients (mean +/- SEM was 102.8 +/- 6.3 microg/ml) as compared to normal controls (27.17 +/- 0.76 microg/ml), assay sensitivity being 91.3%. On an individual basis (n = 25) in patients who were longitudinally monitored for two years, a significant decline in their mean +/- SEM of OD405 was observed from 0.85 +/- 0.06 to 0.28 +/- 0.03. Additionally, a dot-blot was developed to evaluate the proportion of immune-complexed 9-OAcSGs in these patients employing achatinin-H, a 9-OAcSA-binding lectin. Our data indicate that these economically viable ELISA-based approaches allow for reliable, sensitive and rapid diagnosis of ALL. We contend that these disease-specific antibodies could be considered as potential markers both for the initial diagnosis of ALL and possibly for longitudinal monitoring of the disease.

T- cell prolymphocytic leukemia - a rare case.

T- cell Prolymhocytic leukemia (T-PLL) is a rare mature post-thymic T-cell malignancy that is usually reported in the elderly and follows an aggressive course. A 68 year old male presented with a history of weakness and weight loss of two months duration. Clinical examination revealed pallor, enlarged cervical and axillary lymph nodes and splenomegaly. He also had a maculo- papular skin rash. There was marked leucocytosis, anemia and thrombocytopenia (WBC 445 x 103 sub/ml, Hb 8.5 gm/dl, Platelet 25 x 103 sub/microl) with 60% prolymphocytes in the peripheral blood. Bone marrow was hypercellular with an excess of prolymphocytes. Flow cytometric analysis of the bone marrow showed positivity for CD2, CD3, CD4, CD5 and CD 7. T- PLL is a rare T cell disorder with characteristic clinical and laboratory features. Currently, no optimal treatment exists although there has been some success with 2'- deoxycoformycin or Campath-1H.

Protein kinase C isoforms in normal and leukemic neutrophils: altered levels in leukemic neutrophils and changes during myeloid maturation in chronic myeloid leukemia.

Protein kinase C (PKC) is reported to play a role in maturation of the myeloid cell and functions of the mature neutrophil. The neutrophils in chronic myeloid leukemia (CML) exhibit defects in several functions. As a step towards understanding the role of PKC in the defects in function of the leukemic cells, this study investigates the expression of PKC isoforms, their subcellular distribution, levels and kinase activity in the normal and leukemic neutrophils. It also investigates changes in representative PKC isoforms during myeloid maturation. This study confirms the presence of PKC alpha, beta and delta and shows, for the first time, the presence of non conventional PKC isoform theta, atypical PKC isoform lambda/iota and PKC isoform mu in normal human neutrophils. In unstimulated cells all the detected PKC isoforms showed a predominantly cytosolic localisation in normal and CML neutrophils. Cytosol-membrane distribution of PKC alpha and delta were significantly altered in leukemic neutrophils as compared to normal cells. Cytosolic levels of all PKC isoforms were reduced in CML neutrophils with PKC alpha, beta, iota, theta, and mu showing a significant decrease. Cytosolic levels of PKC delta contrary to the trend observed for other PKC isoforms showed a slight increase in CML cells, while its membrane levels were significantly reduced in CML neutrophils. Total PKC kinase activity in CML neutrophil cytosol was significantly reduced, while specific kinase activity of two representative isoforms, PKC alpha and delta, from normal and CML neutrophils were similar, thereby increasing the significance of the altered levels of PKC isoforms in CML, and highlighting their role in the defects in function exhibited by the leukemic neutrophils. The levels of PKC delta and iota increased and decreased respectively as the leukemic myeloid cell matured from the blast to the neutrophil, while the levels of PKC alpha and beta were not altered. This suggests a role for PKC delta and iota in the maturation of the leukemic myeloid cell.